Injectable pharmaceutical composition for treatment and reversal of erectile dysfunction

ABSTRACT

An injectable pharmaceutical composition for treatment of erectile dysfunction. The composition includes prostaglandin E-1, and optionally further includes levsin and/or additional vasodilators such as diltiazem HCl, verapamil, chlorpromazine, d,L-hyoscyamine, and 6,7-dimethoxy-1-veratrylisoquinoline HCl. The composition is effective for long-term restoration of normal erectile function to a patient having erectile dysfunction. The ability to reverse erectile dysfunction may be further enhanced by the inclusion of vitamin B-6, B-12, folic acid, and/or TPA. Also disclosed are methods for treatment and reversal of erectile dysfunction by injecting the pharmaceutical composition into the penis, either by subcutaneous or intracavernosal injection.

[0001] This is a continuation of U.S. application Ser. No. 09/321,693,filed May 28, 1999, which is a continuation-in-part of U.S. applicationSer. No. 09/110,814, filed Jul. 6, 1998, which is a continuation-in-partof U.S. application Ser. No. 09/007,166, filed Jan. 14, 1998. Thisapplication is also a continuation-in-part of U.S. application Ser. No.09/007,142, filed Jan. 14, 1998. The contents of all of the aboveapplications are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to pharmaceutical compositions fortreatment of erectile dysfunction. The invention also relates to methodsof administering the compositions for treatment of erectile dysfunction,including by subcutaneous (sub-q), intramuscular (IM), intracavernosal(IC), intravenous (IV), and intraarterial injection. The inventionfurther relates to methods for reversal of erectile dysfunction byadministering the compositions disclosed herein to a patient in order toimprove penile circulation, which has the long-term benefit of restoringerectile function well after administration of the compositions of theinvention.

BACKGROUND OF THE INVENTION

[0003] Erectile dysfunction is a serious condition which afflicts asignificant percentage of the male population worldwide. This conditionoften has significant psychological effects which can, in severe cases,significantly reduce the quality of life for the person affected. Theeffects are often most severe among elderly male patients, but thiscondition has become increasingly prevalent within the middle-aged, andeven the youthful segments of the male population.

[0004] It is believed that the parasympathetic nerve plays an importantrole in the regulation of erectile function. As noted above, impotenceis most frequent in the elderly male population. Impotence is also afrequent affliction among male patients who have undergoneprostatectomy, either for treatment of prostate cancer or an enlargedprostate condition. In fact, although numerous patients are candidatesfor removal of enlarged prostate, many elect not to have the surgery,and to live with the effects of an enlarged prostate, because they fearloss of normal erectile function. In addition to prostatectomy, severalother causes have been linked to erectile dysfunction, includingdiabetes, psychological causes, surgery (including lower back whichaffects the parasympathetic nerve), trauma, obesity, smoking, or anyother condition which constricts or restricts the arteries or reducesblood flow.

[0005] There are currently five methods available for treatment oferectile dysfunction. First, a prostaglandin-E1 product (Muse, Vivus) isavailable for intra urethral administration. Injectable products includeproducts comprising prostaglandin-E1 for intramuscular/intracavernosalinjection. None of these products interact with all of the importantreceptors or with the parasympathetic nerve. In fact, injectableproducts including only prostaglandin-E1 have been shown to have anefficacy of no greater than 50%. Moreover, none of these products haveshown any efficacy for reversal of erectile dysfunction, and thereforeinjection or administration must be repeated each time an erection isdesired. Further drawbacks of these injectable preparations are thatthey produce pain and unnatural erection, in addition to thedifficulties of injection. In addition to these pharmaceuticaltreatments for erectile dysfunction, implants have also been used fortreatment of erectile dysfunction. These include both permanently rigidimplants (e.g., Erectaid), as well as implants having pumpingcapabilities, and which therefore can be deflated after use.

[0006] Thus, a product is needed for treatment of erectile dysfunctionhaving an efficacy of greater than 50%. Moreover, a product is neededfor reversal of erectile dysfunction, a product for which one or a fewadministrations will restore to the patient normal erectile function.Moreover, a pharmaceutical product is needed for treatment of impotencein male patients who have undergone prostatectomy, surgery (includinglower back which affects the parasympathetic nerve), trauma, or whosuffer from diabetes, psychological causes of impotence, obesity,smoking, or any other condition which constricts or restricts thearteries or reduces blood flow.

SUMMARY OF THE INVENTION

[0007] The present invention relates to injectable pharmaceuticalcompositions as described below for treatment of erectile dysfunction.We have discovered that prostaglandin E-1, in combination with otheragents disclosed herein, can be used successfully as a vasodilator fortreatment of erectile dysfunction, and even for reversal to causerecovery from erectile dysfunction. Thus, in certain embodiments, thepreparation includes prostaglandin E-1 in an amount effective to causeerection in a patient experiencing erectile dysfunction. In anotherembodiment the preparation will include additional vasodilators, such asantimuscarinics, e.g., d,L-hyoscyamine and/or dicyclomine HCl. In otherembodiments the preparation will include further vasodilators, such ascalcium channel blockers, e.g., verapamil and/or diltiazem HCl. In otherembodiments the preparation will also include levsin and/or additionalvasodilators, such as smooth muscle relaxants, e.g.,6,7-dimethoxy-1-veratrylisoquinoline HCl. In other embodiments thepreparation will also include chlorpromazine, a pharmaceutical havingvasodilating action due to its effect on the autonomic nervous systemand direct action on blood vessels.

[0008] The invention also relates to preparations which include one ormore agents to enhance the ability of the preparation to reverseerectile dysfunction by providing long-term improvement of penilecirculation. For example, the injectable pharmaceutical composition ofthe invention may include vitamin B-12, vitamin B-6, folic acid, and/ortissue plasminogen activator.

[0009] The methods of the invention include methods for treatment of apatient having erectile dysfunction, and determination of reversal oferectile dysfunction. The physician provides a pharmaceuticalcomposition having an effective amount of prostaglandin E-1, andoptionally further having effective amounts of one or more of levsin,verapamil and 6,7-dimethoxy-1-veratrylisoquinoline HCL. The patient isinjected with the pharmaceutical composition. The injection willtypically occur in the penis, but may also occur elsewhere in the body.Injection may be subcutaneous, intracavernosal or intramuscular, and mayalso occur systemically (i.e., intravenous or intra-arterial).

[0010] Before, during, and after injection, the patient may bediagnostically monitored to determine the increase in penile hemodynamicfunction (circulation), in order to quantitatively orsemi-quantitatively determine the effectiveness of treatment or reversalof erectile dysfunction. Any diagnostic technique useful to monitor ordetect perfusion or blood circulation may be used. Useful techniquesinclude ultrasound, MRI, CT, and X-ray (fluoroscopy), and any of thesetechniques may further include the use of contrast agents which are wellknown and commercially available. Techniques for measuring hemodynamicparameters include those disclosed in Place, U.S. Pat. No. 5,482,039,incorporated herein by reference.

[0011] In other methods of the invention, the pharmaceutical compositionwill further include effective amounts of additional vasodilatingagents, such as diltiazem HCl, d,L-hyoscyamine, dicyclomine HCl,chlorpromazine. In still other methods, the composition will include oneor more agents which enhance the ability of the preparation to reverseerectile dysfunction by providing long-term improvement of penilecirculation. These compositions thus effect treatment which restoresnormal erectile function to the patient. For example, the injectablepharmaceutical composition may include effective amounts of vitaminB-12, vitamin B-6, folic acid, and/or tissue plasminogen activator. Theinvention can also be used to treat tension headache and to treatAlzheimer's disease.

DETAILED DESCRIPTION

[0012] In a first embodiment the injectable pharmaceutical compositionsfor treatment of erectile dysfunction includes prostaglandin E-1 in anamount effective to cause an erection in a patient experiencing erectiledysfunction. In another embodiment the preparation will also includelevsin and/or additional vasodilators, such as verapamil, and mayoptionally further include 6,7-dimethoxy-1-veratrylisoquinoline HCl. Theeffective amount of prostaglandin E-1 will typically be 0.0001-60 μg,more preferably 0.001-60 μg, more preferably 0.01-60 μg, more preferably0.1-60 μg, more preferably 0.5-20 μg, more preferably 1.0- 10 g. Whenincluded, the effective amount of verapamil will typically be 0.001 - 10μg, more preferably 0.05-5 mg, more preferably 0.1-1 mg. When included,the effective amount of 6,7-dimethoxy-1-veratrylisoquinoline HCl willtypically be 0.0001-60 mg, more preferably 0.001-10 mg, more preferably0.01-1 mg, more preferably 0.1-0.5 mg. All of these pharmaceuticals arecommercially available and the sources are known to those of skill inthe art.

[0013] In other embodiments the preparation will include any of theabove compositions in combination with an effective amount of levsin,which will typically be 0.0001-10 mg, more preferably 0.0005-1 mg, morepreferably 0.001-0.5 mg. Levsin (hyoscyamine sulfate USP) is one of theprincipal anticholinergic/antispasmodic components of belladonnaalkaloids. The empirical formula is (C17H23NO3)2.H2SO4.2H2O and themolecular weight is 712.85. Chemically, it is benzeneacetic acid,alpha-(hydroxymethyl)-,8-methyl-8-azabicyclo(3.2.1.)oct-3-ylester,(3(S)- endo)-,sulfate(2:1),dihydrate. Levsin inhibits specificallythe actions of acetylcholine on structures innervated by postganglioniccholinergic nerves and on smooth muscles that respond to acetylcholinebut lack cholinergic innervation. These peripheral cholinergic receptorsare present in the autonomic effector cells of the smooth muscle, thecardiac muscle, the sinoatrial node, the atrioventricular node, and theexocrine glands. At therapeutic doses, it is completely devoid of anyaction on autonomic ganglia. Levsin inhibits gastrointestinal propulsivemotility and decreases gastric acid secretion. Levsin also controlsexcessive pharyngeal, tracheal and bronchial secretions.

[0014] In other embodiments the preparation will include any of theabove compositions in combination with one or more further vasodilatingagents such as diltiazem HCl in an amount of 0.0001-50 mg, morepreferably 0.001-1 mg, more preferably 0.01-0.5 mg; d,L-hyoscyamine inan amount of 0.0001-10 mg, more preferably 0.0005-1 mg, more preferably0.001-0.5 mg; dicyclomine HCl in an amount of 0-40 mg, more preferably0.1-20 mg, more preferably 0.5-10 mg, more preferably 1-5 mg; orchlorpromazine in an amount of 0.0001-50 mg, more preferably 0.00-10 mg,more preferably 0.01-8 mg, more preferably 1-5 mg.

[0015] Thus, in one embodiment, the composition is a vasodilating amount(10-80%) of prostaglandin-E1. In another embodiment, the compositionfurther includes an effective amount (5-20%) of an antimuscarinic agent(such as dicyclomine HCl or d,L-hyoscyamine). In other embodiments, thecomposition includes any of the above compositions (prostaglandin-E1 orprostaglandin-E1 and antimuscarinic) in combination with an effectiveamount (10-50%) of a calcium channel blocker (such as verapamil ordiltiazem HCl, or other calcium blocker). In still other embodiments,the composition comprises any of the above compositions in combinationwith an effective amount (5-20%) of a smooth muscle relaxant (such as6,7-dimethoxy-1-veratrylisoquinoline HCl). In still other embodiments,the composition comprises any of the above compositions in combinationwith an effective amount (5-20%) of an agent which acts on the autonomicnervous system, such as chlorpromazine.

[0016] In the most preferred embodiment, the composition includes allfive different classes of compounds (vasodilator, antimuscarinic,calcium channel blocker, smooth muscle relaxant, and an agent which actson the autonomic nervous system) in a pharmaceutical preparation. Whenthis pharmaceutical preparation is injected into the penile muscle body(corporal), it causes an increase in blood supply to the penis. Ten tofifteen minutes after injection, an erection results with the ability topenetrate during intercourse. This preparation also works to preventpremature ejaculation.

[0017] In other embodiments the preparation will cure erectiledysfunction by repeated use over a period of time. Thus, administrationof one injection per week for 2 months, more preferably 3 months, morepreferably 4 months, more preferably 5 months, more preferably 6 monthsor more, will cause long-term improvement in penile circulation and thusreversal of erectile dysfunction. More preferably, administration willinclude two injections per week for 2 months, more preferably 3 months,more preferably 4 months, more preferably 5 months, more preferably 6months or more. More preferably, administration will include threeinjections per week for 2 months, more preferably 3 months, morepreferably 4 months, more preferably 5 months, more preferably 6 monthsor more. More preferably, administration will include four injectionsper week for 2 months, more preferably 3 months, more preferably 4months, more preferably 5 months, more preferably 6 months or more. Inother embodiments the preparation will include one or more agents whichenhance the ability of the preparation to reverse erectile dysfunctionby providing long-term improvement of penile circulation. For example,the injectable pharmaceutical composition may include vitamin B-12 in anamount of 0-10 mg, more preferably 0.1-10 mg, more preferably 0.5-8 mg,more preferably 1-5 mg; vitamin B-6 in an amount of 0.000-10 mg, morepreferably 0.001-1 mg, more preferably 0.01-0.8 mg, more preferably0.1-0.5 mg; folic acid in an amount of 0.0001-10 mg, more preferably0.001-0.8 mg, more preferably 0.01-0.6 mg; and/or tissue plasminogenactivator in an amount of 0-1 mg, more preferably 0.1-0.8 mg, morepreferably 0.3-0.6 mg.

[0018] The pharmaceutical preparations may be formulated neat, or usingany of a number of pharmaceutical carriers, diluents, or excipients wellknown in the art. For details, the reader is referred to the Remmingtoncatalog, incorporated herein by reference. For example, in certaincases, a pharmaceutical carrier of benzyl alcohol, chlorobutanol, sodiumchloride, Bacteriostatic water, and normal saline is used. Theinjectable composition will typically have a total volume ofapproximately 0.0005-1 cc, more preferably 0.001-0.5 cc, more preferably0.01-0.1 cc. A volume of 0.01 cc will suffice to give a 50 min erection.In certain other embodiments, the pharmaceutical compositions willcomprise oral tablets, such as for example capsules, caplets, gel caps,syrup, swallow tablets, chewable tablets, and the like.

[0019] The methods disclosed herein are for treatment of a patienthaving erectile dysfunction. The methods include the steps of providinga pharmaceutical composition having an effective amount of prostaglandinE-1, and optionally further having effective amounts of one or both ofverapamil and 6,7-dimethoxy-1-veratrylisoquinoline HCL. The patient isinjected with the pharmaceutical composition. The injection willtypically occur in the penis, but may also occur elsewhere in the body.Injection may be subcutaneous, intramuscular, or intracavernosal, andmay also occur systemically (i.e., intravenous or intra-arterial). Forintracavernosal injection a one-third inch needle penetration issufficient.

[0020] In other methods, the pharmaceutical composition will furtherinclude effective amounts of additional vasodilating agents, such asdiltiazem HCl, d,L-hyoscyamine, dicyclomine HCl, chlorpromazine. Instill other methods, the composition will include one or more agentswhich enhance the ability of the preparation to reverse erectiledysfunction by providing long-term improvement of penile circulation.These compositions thus effect treatment which restores normal erectilefunction to the patient. For example, the injectable pharmaceuticalcomposition may include effective amounts of vitamin B-12, vitamin B-6,folic acid, and/or tissue plasminogen activator.

[0021] The compositions disclosed herein are characterized in that theyare at least about 60% effective for treatment of erectile dysfunction,whereas existing pharmaceutical preparations are no more than 50%effective. Preferred compositions disclosed herein are at least about70% effective for treatment of erectile dysfunction, more preferably atleast about 80% effective, more preferably at least about 90% effective,more preferably at least about 95% effective. The compositions hereinare characterized in that they stimulate the parasympathetic nerve forimprovement of erectile function. The disclosed compositions moreoveract on one or more receptor cites for vasodilation, more preferably twoor more receptors, more preferably three or more receptors, morepreferably four or more receptors, most preferably five or morereceptors. The disclosed compositions are also characterized in thatthey are effective for treatment of impotence associated withprostatectomy, surgery (including lower back which affects theparasympathetic nerve), trauma, diabetes, psychological causes ofimpotence, obesity, smoking, or any other condition which constricts orrestricts the arteries or reduces blood flow.

EXAMPLE 1

[0022] A first pharmaceutical composition suitable for eitherintramuscular, intracavernosal, or subcutaneous injection is prepared toinclude the following materials:

[0023] prostaglandin E-150 μg

[0024] verapamil 0.1 mg

[0025] 6,7-dimethoxy-1-veratrylisoquinoline HCl 90 mg

[0026] d,L-hyoscyamine 0.1 mg

[0027] chlorpromazine 0.2 mg

[0028] benzyl alcohol 0.445%w/v

[0029] chlorobutanol 0.5%

[0030] sodium chloride 0.5 mg

[0031] Bacteriostatic water 1 mL

[0032] total volume 1 mL

EXAMPLE 2

[0033] A second pharmaceutical composition suitable for eitherintramuscular, intracavernosal, or subcutaneous injection is prepared toinclude the following materials: Total Used Total Used 1 unit IngredientmL in mg. per mL [100 units = 1 mL] chlorpromazine 3/75 5.357143 0.0536d,L-hyoscyamine 3/1.2 0.085714 0.0009 dihiazem HCl 2/10 0.714286 0.00716,7-dimethoxy-1- 6/180 12.85714 0.1286 veratrylisoquinoline HClprostaglandin E-1 40 mcg 2.857143 0.0286 Total 14

[0034] According to this formula, 0.01 cc will suffice to give a 50minute erection. This preparation is also effective for treatment ofpremature ejaculation.

EXAMPLE 3

[0035] A preparation made according to Example 1 was administered to a43-year-old male patient LD with a history of premature ejaculation. A0.1 cc dose of formulated solution was injected intracavernosally intothe penis. He experienced continuous sexual activity for 3 hours.

EXAMPLE 4

[0036] A preparation made according to Example 1 was administered to a47-year-old male patient EH. The patient had experienced, over a periodof 2-3 years, a gradual decline in his ability to maintain an erectionfor the entire duration of intercourse. He experienced a 6-hour erection(i.e., priapism) after injection of 0.23 cc formulated solutionintracavernosally into the penis. Moreover, this treatment with theformulated solution actually restored his ability to maintain a strongerection for the entire duration of intercourse on subsequent occasions,even without having further injections. Thus, IC administration of theformulation disclosed herein demonstrated a reversal of erectiledysfunction.

EXAMPLE 5

[0037] A preparation made according to Example 1 was administered to a48-year-old male patient WL. He experienced a 2-hour erection afterinjection of 0.27 cc formulated solution intracavernosally into thepenis.

EXAMPLE 6

[0038] A preparation made according to Example 1 was administered to a47-year-old obese male patient PP. He experienced a 1-hour erectionafter injection of 0.20 cc formulated solution intracavernosally intothe penis.

EXAMPLE 7

[0039] A preparation made according to Example 1 is administered to a50-year-old male patient having a history of prostate inflammation andhaving undergone prostate removal. He experiences a 1-hour erectionafter injection of 0.20 cc formulated solution intracavernosally intothe penis.

EXAMPLE 8

[0040] A preparation made according to Example 1 is administered to a50-year-old male patient. He experiences a 1-hour erection afterinjection of 0.20 cc formulated solution subcutaneously into the penis.

EXAMPLE 9

[0041] A preparation made according to Example 2 is administered to amale patient. He experiences a 1-hour erection after injection of 0.01cc formulated solution IC into the penis.

EXAMPLE 10

[0042] A preparation made according to Example 2 is administered to amale patient. He experiences a 6-hour erection after injection of 0.01cc formulated solution IC into the penis.

EXAMPLE 11

[0043] Two male patients, AA and BB, are selected, both suffering fromimpotence. Penile circulation is monitored by ultrasound to determinebaseline circulation readings. A preparation made according to Example 1is administered to AA by intracavernosal injection into the penis.Patient BB receives intracavernosal injection of placebo. Penilecirculation is again monitored by ultrasound to determine enhancedcirculation readings at t=0. Each week AA and BB are tested in this samemanner, and pre- and post-injection circulation readings are recorded.The study is continued for 6-months. After 6-months, injections arediscontinued, and only ultrasound recordings are continued for anadditional 6-month period.

[0044] The results of this study are as follows. During the first6-month period, pre-injection circulation readings are consistentlyhigher for AA than for BB, with the exception of the readings at t=0.Moreover, the difference between circulation readings for AA and BBincreases with each succeeding week. During the second 6-month period,circulation readings are consistently higher for AA than for BB. Thedifference between circulation readings for AA and BB remainsapproximately constant.

EXAMPLE 12

[0045] The invention can also be used to treat tension headache and totreat Alzheimer's disease. Two patients, TL and EH, were selected, bothsuffering from tension headache. A preparation made according to Example1 is administered to TL and EH. The tension headache resolved in a shorttime.

[0046] While particular compositions and methods have been describedherein, once this description is known, it will be apparent to those ofordinary skill in the art that other embodiments and alternative stepsare also possible without departing from the spirit and scope of theinvention. Moreover, it will be apparent that certain features of eachembodiment as well as features disclosed in each reference incorporatedherein can be used in combination with features illustrated in otherembodiments. Accordingly, the above description should be construed asillustrative, and not in a limiting sense, the scope of the inventionbeing defined by the following claims.

What is claimed is:
 1. A method for treatment of a patient havingerectile dysfunction, comprising the steps of: providing apharmaceutical composition comprising 0.0001-60 μg prostaglandin E-1 andd,L-hyoscyamine; and injecting the patient with the pharmaceuticalcomposition.
 2. The method of claim 1 , wherein the pharmaceuticalcomposition further comprises a calcium channel blocker.
 3. The methodof claim 1 , wherein the step of injecting the patient with thepharmaceutical composition includes the use of a needle.
 4. The methodof claim 1 , wherein the treatment restores normal erectile function tothe patient.
 5. The method of claim 1 , wherein the injection issubcutaneous.
 6. The method of claim 1 , wherein the injection isintracavernosal.
 7. The method of claim 1 , wherein the pharmaceuticalcomposition further comprises 0-10 mg vitamin B-12.
 8. The method ofclaim 1 , wherein the pharmaceutical composition further comprises 0-10mg vitamin B-6.
 9. The method of claim 1 , wherein the pharmaceuticalcomposition further comprises 0-1 mg folic acid.